U.S. patent number 6,893,685 [Application Number 09/939,145] was granted by the patent office on 2005-05-17 for process for surface modifying substrates and modified substrates resulting therefrom.
This patent grant is currently assigned to Novartis AG. Invention is credited to Peter Chabrecek, Hans Griesser, Peter Kambouris, John Martin Lally, Paul Pasic, Yongxing Qiu, Lynn Cook Winterton.
United States Patent |
6,893,685 |
Qiu , et al. |
May 17, 2005 |
Process for surface modifying substrates and modified substrates
resulting therefrom
Abstract
The invention relates to a process for coating a material
surface, comprising the steps of: (a) applying to the material
surface a tie layer comprising a polyionic material; (b) covalently
binding a bifunctional compound comprising an ethylenically
unsaturated double b3nd to the tie layer; and (c) graft
polymerizing a hydrophilic monomer onto the compound comprising the
ethylenically unsaturated double bond. The coated articles that are
obtainable by the process of the invention have desirable
characteristics regarding adherences to the substrate, durability,
hydrophilicity, wettability, biocompatibility and permeability and
are thus useful for the manufacture of biomedical articles such as
ophthalmic devices.
Inventors: |
Qiu; Yongxing (Duluth, GA),
Winterton; Lynn Cook (Alpharetta, GA), Lally; John
Martin (Lilburn, GA), Pasic; Paul (Melbourne,
AU), Griesser; Hans (The Patch, AU),
Kambouris; Peter (Carindale, AU), Chabrecek;
Peter (Riehen, CH) |
Assignee: |
Novartis AG (Basel,
CH)
|
Family
ID: |
26245819 |
Appl.
No.: |
09/939,145 |
Filed: |
August 24, 2001 |
Current U.S.
Class: |
427/407.1;
428/520; 428/515; 428/451; 428/447; 427/412.1; 427/2.12; 427/2.13;
427/2.24; 351/159.02 |
Current CPC
Class: |
G02B
1/043 (20130101); A61L 27/34 (20130101); C08J
7/16 (20130101); Y10T 428/31928 (20150401); Y10T
428/31663 (20150401); Y10T 428/31511 (20150401); Y10T
428/31909 (20150401); Y10T 428/31667 (20150401) |
Current International
Class: |
A61L
27/00 (20060101); A61L 27/34 (20060101); G02B
1/04 (20060101); B05D 001/36 () |
Field of
Search: |
;427/2.12,2.13,2.24,407.1,412.1 ;428/447,451,515,520
;351/159,160R |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
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Other References
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Molecules, D. Yoo, et al., Material Resource, Soc. Symp. Proc. vol.
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Vargo, et al, Supramolecular Science, vol. 2, Nos. 3-4, 1995, ppg
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Abstract, JP 05318118, Matsumoto, Dec. 1993..
|
Primary Examiner: Buttner; David J.
Assistant Examiner: Keehan; Christopher
Attorney, Agent or Firm: Zhou; Jian Gorman; Robert Meece; R.
Scott
Parent Case Text
CROSS-REFERENCE TO RELATED APPLICATION
This application claims the benefit of provisional application No.
60/228,022, filed Aug. 24, 2000.
Claims
What is claimed is:
1. A process for coating a material surface, comprising the steps
of: (a) applying to the material surface a tie layer comprising a
polyionic material; (b) covalently binding a bifunctional compound
comprising an ethylenically unsaturated double bond to the tie
layer; and (c) graft polymerizing a hydrophilic monomer onto the
compound comprising the ethylenically unsaturated double bond.
2. A process according to claim 1, wherein the material surface is
the surface of an organic bulk material, in particular the surface
of a biomedical device comprising an organic bulk material.
3. A process according to claim 1 or 2, wherein the tie layer of
step (a) consists of one single polyionic material.
4. A process according to claim 1 or 2, wherein the tie layer of
step (a) includes at least one bilayer comprising a polycationic
material and a polyanionic material.
5. A process according to any one of claim 1, wherein the polyionic
material of the tie layer comprises one or more polymers selected
from the group consisting of a poly(allylamine hydrochloride), a
poly(ethyleneimine), a poly(acrylic acid), and a poly(methacrylic
acid).
6. A process according to any one of the claim 1, wherein the
covalent bonding between the tie layer and the bifunctional
compound comprising an ethylenically unsaturated double bond occurs
via reaction of a hydroxy, amino, alkylamine, thiol or carboxy
group, of the tie layer with an isocyanato, azlactone, epoxy,
carboxy anhydride, carboxy or hydroxy group, of the ethylenically
unsaturated compound.
7. A process according to any one of claim 1, wherein the
ethylenically unsaturated compound is of formula: ##STR4##
wherein R.sub.1 is hydrogen, C.sub.1 -C.sub.4 -alkyl or halogen;
R.sub.2 is hydrogen, unsubstituted or hydroxy-substituted C.sub.1
-C.sub.6 -alkyl or phenyl; R.sub.3 and R.sub.3 ' are each an
ethylenically unsaturated radical having from 2 to 6 C-atoms, or
R.sub.3 and R.sub.3 ' together form a bivalent radical
--C(R.sub.4).dbd.C(R.sub.4 ')-- wherein R.sub.4 and R.sub.4 ' are
each independently hydrogen, C.sub.1 -C.sub.4 -alkyl or halogen and
(Alk*) is C.sub.1 -C.sub.6 -alkylene, and (Alk**) is C.sub.2
-C.sub.12 -alkylene.
8. A process according to claim 7, wherein, in step (b), the
compound comprising an ethylenically unsaturated double bond is of
formula (2a).
9. A process according to any one of the claim 1, wherein, in step
c), the hydrophilic monomer is selected from the group consisting
of acrylamide, acrylic acid, methacrylic acid, hydroxyethyl
methacrylate, hydroxyethyl acrylate, methacrylamide,
N,N-dimethylacrylamide, allylalcohol, N-vinylpyrrolidone and
N,N-dimethylaminoethyl acrylate.
10. A process according to any one of claim 1, wherein in step (c),
the monomer comprises one or more different monomers at least one
of them comprising a reactive group.
11. A process according to any one of the claim 1, wherein in step
(c), the monomer comprises a reactive group, (i) said reactive
groups are reacted with a further compound comprising an
ethylenically unsaturated double bond, (ii) a hydrophilic monomer
and optionally a co-monomer having a crosslinkable group are
graft-polymerized to said ethylenically unsaturated double bond,
and (iii) in case crosslinkable groups being present in step (ii),
crosslinking of said groups is initiated.
12. A process according to claim 11, wherein, in step (i), the
further compound comprising an ethylenically unsaturated double
bond is a compound of formula (2a)-(2e) according to claim 7.
13. A process according to claim 12, wherein, in step (ii) the
hydrophilic monomer is selected from the group consisting of
acrylic acid, acrylamide, N,N-dimethylacrylamide and
N-vinylpyrrolidone and no co-monomer having a crosslinking group is
present.
14. A coated material that is obtainable by the process of any one
of the claim 1.
15. A coated material according to claim 14, which is a biomedical
device.
16. A coated material according to claim 15, which is an ophthalmic
device.
17. A coated material according to claim 16, which is a contact
lens, intraocular lens or artificial cornea.
Description
FIELD OF THE INVENTION
The present invention generally relates to a method of modifying
the surface of substrates such as contact lenses and other
biomedical articles by at least partially coating the surfaces of
such substrates with a reactive polymeric tie layer.
BACKGROUND OF THE INVENTION
Many devices used in biomedical applications require that the bulk
of the device have one property and the surface of the device have
a different property. For example, contact lenses may require
relatively high oxygen permeability through the bulk of the lens to
maintain good corneal health. However, materials that exhibit
exceptionally high oxygen permeability (e.g. polysiloxanes) are
typically hydrophobic and, untreated or not surface modified, will
adhere to the eye. Thus a contact lens will generally have a core
bulk material that is highly oxygen permeable and hydrophobic, and
a surface that has been treated or coated to increase hydrophilic
properties. This hydrophilic surface allows the lens to move
relatively freely on the eye without adhering excessive amounts of
tear lipid and protein.
A known method for modifying the hydrophilicity of a relatively
hydrophobic contact lens material is through the use of a plasma
treatment. Plasma treatment techniques are disclosed, for example,
in PCT Publications Nos. WO 96/31793 to Nicolson et al., WO
99/57581 to Chabrecek et al., and WO 94/06485 to Chatelier et al.
In the Chabrecek et al. application, photoinitiator molecules are
covalently bound to the surface of the article after the article
has been subjected to a plasma treatment which provides the surface
with functional groups. A layer of polymerizable macromonomer is
then coated onto the modified surface and heat or radiation is
applied to graft polymerise the macromer to form the hydrophilic
surface.
Plasma treatment processes, however, require a significant capital
investment in plasma processing equipment. Moreover, plasma
treatments take place in a vacuum and, thus, require that the
substrate be mostly dry before exposure to the plasma. Thus,
substrates, such as contact lenses, that are wet from prior
hydration or extraction processes must be dried, thereby further
adding to both the capital and production costs. As a result of the
conditions necessary for plasma treatment, the incorporation of a
plasma treatment process into an automated production process is
extremely difficult.
Other methods of permanently altering the surface properties of
polymeric biomaterials, such as contact lenses, have been
developed. Some of these techniques include Langmuir-Blodgett
deposition, controlled spin casting, chemisorptions, and vapor
deposition. Examples of Langmuir-Blodgett layer systems are
disclosed in U.S. Pat. Nos. 4,941,997; 4,973,429, and 5,068,318.
Like plasma treatment, these techniques are not cost-effective
methods that may easily be incorporated into automated production
processes for making biomedical devices such as contact lenses.
A more recent technique developed for coating substrates is a
layer-by-layer ("LbL") polymer absorption process, which is
described, for example, in WO 99/35520 to Winterton at al., which
concerns the absorption of polyionic compounds on "inert"
materials.
SUMMARY OF THE INVENTION
Some of the shortcomings of the prior art are overcome with the
present invention, which is directed to a method for modifying the
surface of substrates, such as contact lenses and other biomedical
articles, by at least partially coating the surfaces of such
substrates with a reactive tie layer. The reactive polymeric tie
layer, which is generally deposited onto the substrate surface as a
polyelectrolytic layer, provides reactive sites for the attachment
of, for example, a further hydrophilic polymer coating. In other
words, the polymeric tie layer creates active moieties on the
substrate surface trough functionalization of the surface by
coating with a polyanion and/or polycation. Additional chemistry,
such as condensation reactions, free radical-initiated
polymerization reactions, and the like, can then be performed on
these active moieties by reacting the moieties with various
agents.
Various methods can be utilized to attach the reactive moieties of
the polymeric tie layer to the substrate surface. One such method
for creating the reactive sites is a layer-by-layer coating
application that utilizes successive dips, sprays, or other
applications of first a polyanionic layer, and then a polycationic
layer. Additional polyelectrolytic layers may be applied by this
successive application method. Another method applicable to the
present invention is a single dip method that utilizes a
bicomponent solution containing both a polycationic substance and a
polyanionic substance in a single solution.
Among the various polyelectrolytes that can be utilized in such
polymeric tie layer coating processes are polyacrylic acid and
poly(allylamine hydrochloride). For example, a polyacrylic acid
coating will provide carboxyl functional groups (--COOH) on the
surface; and a poly(allylamine hydrochloride) coating will provide
amino functional groups (--NH.sub.2) on the surface. These reactive
groups may then be further reacted with additional desired
molecules or compounds such as functional monomers.
The present invention therefore in one aspect relates to a process
for coating a material surface, comprising the steps of: (a)
applying to the material surface a tie layer comprising a polyionic
material; (b) covalently binding a bifunctional compound comprising
an ethylenically unsaturated double bond to the tie layer; and (c)
graft polymerizing a hydrophilic monomer onto the compound
comprising the ethylenically unsaturated double bond.
DETAILED DESCRIPTION OF REPRESENTATIVE EMBODIMENTS
Reference now will be made in detail to the embodiments of the
invention, one or more examples of which are set forth below. Each
example is provided by way of explanation of the invention, not
limitation of the invention. In fact, it will be apparent to those
skilled in the art that various modifications and variations can be
made in the present invention without departing from the scope or
spirit of the invention. For instance, features illustrated or
described as part of one embodiment, can be used on another
embodiment to yield still a further embodiment. Thus, it is
intended that the present invention cover such modifications and
variations as come within the scope of the appended claims and
their equivalents. Other objects, features and aspects of the
present invention are disclosed in or are obvious from the
following detailed description. It is to be understood by one of
ordinary skill in the art that the present discussion is a
description of exemplary embodiments only, and is not intended as
limiting the broader aspects of the present invention.
The present invention is generally directed to the modification of
a substrate surface by utilizing a method of coating the surface
with various polyionic functional groups. The polycationic and/or
polyanionic functional groups provide reactive sites to which
various other chemical substances may be bound through traditional
or non-traditional chemical reactions or attachment mechanisms.
In accordance with the present invention, a coating process is
provided that can be utilized to deposit polyionic materials onto a
substrate to form polymeric tie layers having functional groups
thereon so that additional active agents can be attached thereto.
In one embodiment, for example, a process of the present invention
allows the deposition of a bicomponent polyionic solution to a
biomaterial substrate, such as a contact lens.
In accordance with the present invention, a polyionic solution is
employed to coat the substrate. In general, the polyionic solution
contains at least one polycationic material and at least one
polyanionic material, although more than one of each polyionic
material can be employed. In one embodiment, for example, the
polyionic solution is a bicomponent solution containing a
polycation and a polyanion.
Typically, a polycationic material of the present invention can
include any material known in the art to have a plurality of
positively charged groups along a polymer chain, such as a
poly(allylamine hydrochloride). Likewise, a polyanionic material of
the present invention can typically include any material known in
the art to have a plurality of negatively charged groups along a
polymer chain, such as polyacrylic acid.
According to one embodiment of the present invention, a
polycationic material is combined with a polyanionic material to
form a "single-dip" polyionic solution. In general, the polyionic
components are added in non-stoichometric amounts such that one of
the components is present within the solution in a greater amount
than another component of opposite charge. In particular, the molar
charge ratio, as defined herein, can be from about 3:1 to about
100:1. In certain embodiments, the molar charge ratio is 10:1
(polyanion:polycation).
Layers of polyionic components can be coated onto the substrate.
For example, in one embodiment,
polyanionic-polycationic-polyanionic alternating repeating layers
are assembled when the substrate is dipped into the solution.
Besides containing polyionic components, a polyionic solution of
the present invention can also contain various other materials. For
example, the polyionic solution can contain antimicrobials,
antibacterials, radiation-absorbing materials, cell growth
inhibitors, etc.
In other embodiments, the substrate can be dipped sequentially into
separately charged polyionic solutions. In these embodiments, a
solution of polycationic material may be the first stage dip and a
solution of polyanionic material may be the second stage dip (or
vice versa). Additional polyionic materials may be utilized.
In general, a surface modified device of the present invention can
be made from various materials. Examples of suitable substrate
materials include quartz, ceramics, glasses, silicate materials,
silica gels, metals, metal oxides, carbon materials such as
graphite or glassy carbon, natural or synthetic organic polymers,
or laminates, composites or blends of such materials, including
natural or synthetic organic polymers or modified biopolymers which
are well-known. Examples of polymers include polyaddition and
polycondensation polymers (polyurethanes, epoxy resins, polyethers,
polyesters, polyamides and polyimides); vinyl polymers
(polyacrylates, polymethacrylates, polyacrylamides,
polymethacrylamides, polystyrene, polyethylene and halogenated
derivatives thereof, polyvinylacetate and polyacrylonitrile); or
elastomers (silicones, polybutadiene and polyisoprene).
A particular group of bulk materials from which the inventive
substrates may be formed comprises organic polymers selected from
polyacrylates, polymethacrylates, poly(N,N-dimethylacrylamides),
polymethacrylamides, polyvinyl acetates, polysiloxanes,
perfluoroalkyl polyethers, fluorinated polyacryalates or
-methacrylates and amphiphilic segmented copolymers comprising at
least one hydrophobic segment, for example a polysiloxane or
perfluoroalkyl polyether segment or a mixed
polysiloxane/perfluoroalkyl polyether segment, and at least one
hydrophilic segment, for example a polyoxazoline,
poly(2-hydroxyethylmethacrylate), polyacrylamide,
poly(N,N-dimethylacrylamide), polyvinylpyrrolidone polyacrylic or
polymethacrylic acid segment or a copolymeric mixture of two or
more of the underlying monomers.
A preferred group of materials to be coated are those being
conventionally used for the manufacture of biomedical devices, e.g.
contact lenses, in particular contact lenses for extended wear,
which are not hydrophilic per se. Such materials are known to the
skilled artisan and may comprise for example polysiloxanes,
perfluoroalkyl polyethers, fluorinated poly(meth)acrylates or
equivalent fluorinated polymers derived e.g. from other
polymerizable carboxylic acids, polyalkyl (meth)acrylates or
equivalent alkylester polymers derived from other polymerizable
carboxylic acids, or fluorinated polyolefines, such as fluorinated
ethylene or propylene, for example tetrafluoroethylene, preferably
in combination with specific dioxols, such as
perfluoro-2,2-dimethyl-1,3-dioxol. Examples of suitable bulk
materials are e.g. Lotrafilcon A, Neofocon, Pasifocon, Telefocon,
Silafocon, Fluorsilfocon, Paflufocon, Silafocon, Elastofilcon,
Fluorofocon or Teflon AF materials, such as Teflon AF 1600 or
Teflon AF 2400 which are copolymers of about 63 to 73 mol % of
perfluoro-2,2-dimethyl-1,3-dioxol and about 37 to 27 mol % of
tetrafluoroethylene, or of about 80 to 90 mol % of
perfluoro-2,2-dimethyl-1,3-dioxol and about 20 to 10 mol % of
tetrafluoroethylene.
Another group of preferred materials to be coated is amphiphilic
segmented copolymers comprising at least one hydrophobic segment
and at least one hydrophilic segment which are linked through a
bond or a bridge member. Examples are silicone hydrogels, for
example those disclosed in PCT applications WO 96/31792 to Nicolson
et al. and WO 97/49740 to Hirt et al.
A particular preferred group of bulk materials comprises organic
polymers selected from polyacrylates, polymethacrylates,
polyacrylamides, poly(N,N-dimethylacrylamides),
polymethacrylamides, polyvinyl acetates, polysiloxanes,
perfluoroalkyl polyethers, fluorinated polyacrylates or
-methacrylates and amphiphilic segmented copolymers comprising at
least one hydrophobic segment, for example a polysiloxane or
perfluoroalkyl polyether segment or a mixed
polysiloxane/perfluoroalkyl polyether segment, and at least one
hydrophilic segment, for example a polyoxazoline,
poly(2-hydroxyethylmethacrylate), polyacrylamide,
poly(N,N-dimethylacrylamide), polyvinylpyrrolidone polyacrylic or
polymethacrylic acid segment or a copolymeric mixture of two or
more of the underlying monomers.
The material to be coated may also be any blood-contacting material
conventionally used for the manufacture of renal dialysis
membranes, blood storage bags, pacemaker leads or vascular grafts.
For example, the material to be modified on its surface may be a
polyurethane, polydimethylsiloxane, polytetrafluoroethylene,
polyvinylchloride, Dacron.TM. or Silastic.TM. type polymer, or a
composite made therefrom.
Moreover, the material to be coated may also be an inorganic or
metallic base material without suitable reactive groups, e.g.
ceramic, quartz, or metals, such as silicon or gold, or other
polymeric or non-polymeric substrates. E.g. for implantable
biomedical applications, ceramics are very useful. In addition,
e.g. for biosensor purposes, hydrophilically coated base materials
are expected to reduce nonspecific binding effects if the structure
of the coating is well controlled. Biosensors may require a
specific carbohydrate coating on gold, quartz, or other
non-polymeric substrates.
The form of the material to be coated may vary within wide limits.
Examples are particles, granules, capsules, fibers, tubes, films or
membranes, preferably moldings of all kinds such as ophthalmic
moldings, for example intraocular lenses, artificial cornea or in
particular contact lenses.
Suitable substances that may be utilized to form the polymeric tie
layer of the present invention include various polyionic materials.
One such suitable layer may be formed from a first and second ionic
polymer having opposite charges, wherein the "first ionic polymer"
indicates the polymer that is first of all applied to the article
surface, and the "second ionic polymer" indicates the polymer that
is applied to the article surface after it has already been
modified with the first ionic polymer. The bulk material may
comprise as the tie layer one or more than one such polymeric
layers. For example, from 1 to 50 layers containing the same or
different ionic polymers in each case, from 1 to 25 layers, from 1
to 20 layers, from 1 to 10 layers, from 1 to 5 layers, or just one
layer may be utilized to form the tie layer.
In addition, it may be desirous to have only partial tie layer
coverage on the article being treated so that an incomplete tie
layer is formed. This may be particularly helpful if only one side
of the article needs to be surface modified or if it is desirous to
have the two sides of, for example, a contact lens, to have two
different coatings--one for the front of the lens and one for the
cornea side of the lens.
The polyionic materials that may be employed in the present tie
layer include polyanionic and polycationic polymers. Examples of
suitable anionic polymers include, for example, a synthetic
polymer, a biopolymer or modified biopolymer comprising carboxy,
sulfo, sulfato, phosphono or phosphato groups or a mixture thereof,
or a salt thereof, for example, a biomedical acceptable salt and
especially an ophthalmically acceptable salt thereof when the
substrate to be coated is an ophthalmic device.
Examples of synthetic anionic polymers are: a linear polyacrylic
acid (PAA), a branched polyacrylic acid, for example a
Carbophil.RTM. or Carbopol.RTM. type from Goodrich Corp., a
polymethacrylic acid (PMA), a polyacrylic acid or polymethacrylic
acid copolymer, for example a copolymer of acrylic or methacrylic
acid and a further vinylmonomer, for example acrylamide,
N,N-dimethyl acrylamide or N-vinylpyrrolidone, a maleic or fumaric
acid copolymer, a poly(styrenesulfonic acid) (PSS), a polyamido
acid, for example a carboxy-terminated polymer of a diamine and a
di- or polycarboxylic acid, for example carboxy-terminated
Starburst.TM. PAMAM dendrimers (Aldrich), a
poly(2-acrylamido-2-methylpropanesulfonic acid) (poly-(AMPS)), or
an alkylene polyphosphate, alkylene polyphosphonate, carbohydrate
polyphosphate or carbohydrate polyphosphonate, for example a
teichoic acid.
Examples of anionic biopolymers or modified biopolymers are:
hyaluronic acid, glycosaminoglycanes such as heparin or chondroitin
sulfate, fucoidan, poly-aspartic acid, poly-glutamic acid,
carboxymethyl cellulose, carboxymethyl dextranes, alginates,
pectins, gellan, carboxyalkyl chitins, carboxymethyl chitosans,
sulfated polysaccharides.
A preferred anionic polymer is a linear or branched polyacrylic
acid or an acrylic acid copolymer. A more preferred anionic polymer
is a linear or branched polyacrylic acid. A branched polyacrylic
acid in this context is to be understood as meaning a polyacrylic
acid obtainable by polymerizing acrylic acid in the presence of
suitable (minor) amounts of a di- or polyvinyl compound.
A suitable cationic polymer as part of the bilayer is, for example,
a synthetic polymer, biopolymer or modified biopolymer comprising
primary, secondary or tertiary amino groups or a suitable salt
thereof, preferably an ophthalmically acceptable salt thereof, for
example a hydrohalogenide such as a hydrochloride thereof, in the
backbone or as substituents. Cationic polymers comprising primary
or secondary amino groups or a salt thereof are preferred.
Examples of synthetic cationic polymers are: (i) a polyallylamine
(PAH) homo- or copolymer, optionally comprising modifier units;
(ii) a polyethyleneimine (PEI); (iii) a polyvinylamine homo- or
copolymer, optionally comprising modifier units; (iv) a
poly(vinylbenzyl-tri-C.sub.1 -C.sub.4 -alkylammonium salt), for
example a poly(vinylbenzyl-tri-methyl ammoniumchloride); (v) a
polymer of an aliphatic or araliphatic dihalide and an aliphatic
N,N,N',N'-tetra-C.sub.1 -C.sub.4 -alkyl-alkylenediamine, for
example a polymer of (a) propylene-1,3-dichloride or -dibromide or
p-xylylene dichloride or dibromide and (b)
N,N,N',N'-tetramethyl-1,4-tetramethylene diamine; (vi) a
poly(vinylpyridine) or poly(vinylpyridinium salt) homo- or
copolymer; (vii) a poly (N,N-diallyl-N,N-di-C.sub.1 -C.sub.4
-alkyl-ammoniumhalide) comprising units of formula: ##STR1##
wherein R.sub.2 and R.sub.2 ' are each independently C.sub.1
-C.sub.4 -alkyl, in particular methyl, and An.sup.- is a, for
example, a halide anion such as the chloride anion; (viii) a homo-
or copolymer of a quaternized di-C.sub.1 -C.sub.4 -alkyl-aminoethyl
acrylate or methacrylate, for example a
poly(2-hydroxy-3-methacryloylpropyltri-C.sub.1 -C.sub.2
-alkylammonium salt) homopolymer such as a a
poly(2-hydroxy-3-methacryloylpropyltri-methylammonium chloride), or
a quaternized poly(2-dimethylaminoethyl methacrylate or a
quaternized poly(vinylpyrrolidone-co-2-dimethylaminoethyl
methacrylate); (ix) POLYQUAD.RTM. as disclosed in EP-A-456,467; or
(x) a polyaminoamide (PAMAM), for example a linear PAMAM or a PAMAM
dendrimer such as an amino-terminated Starburst.TM. PAMAM dendrimer
(Aldrich).
The above mentioned polymers comprise in each case the free amine,
a suitable salt thereof, for example a biomedically acceptable salt
or in particular an ophthalmically acceptable salt thereof, as well
as any quaternized form, if not specified otherwise.
Suitable comonomers optionally incorporated in the polymers
according to (i), (iii), (vi) or (viii) above are, for example,
hydrophilic monomers such as acrylamide, methacrylamide,
N,N-dimethyl acrylamide, N-vinylpyrrolidone and the like.
Suitable modifier units of the polyallylamine (i) are known, for
example from WO 00/31150 and comprise, for example, units of
formula: ##STR2##
wherein L is C.sub.2 -C.sub.6 -alkyl which is substituted by two or
more same or different substituents selected from the group
consisting of hydroxy, C.sub.2 -C.sub.5 -alkanoyloxy and C.sub.2
-C.sub.5 -alkylaminocarbonyloxy.
Preferred substituents of the alkyl radical L are hydroxy,
acetyloxy, propionyloxy, methylaminocarbonyloxy or
ethylaminocarbonyloxy, especially hydroxy, acetyloxy or
propionyloxy and in particular hydroxy.
L is preferably linear C.sub.3 -C.sub.6 -alkyl, more preferably
linear C.sub.4 -C.sub.5 -alkyl, and most preferably n-pentyl, which
is in each case substituted as defined above. A particularly
preferred radical L is 1,2,3,4,5-pentahydroxy-n-pentyl.
Examples of cationic biopolymers or modified biopolymers that may
be employed in the tie layer of the present invention include:
basic peptides, proteins or glucoproteins, for example, a
poly-.epsilon.-lysine, albumin or collagen, aminoalkylated
polysaccharides such as a chitosan or aminodextranes.
Particular cationic polymers for forming the polymer tie layer that
are attached to the bulk material of the present invention include
a polyallylamine homopolymer; a polyallylamine comprising modifier
units of the above formula (1); a polyvinylamine homo- or
-copolymer or a polyethyleneimine homopolymer, in particular a
polyallylamine or polyethyleneimine homopolymer, or a
poly(vinylamine-co-acrylamid) copolymer.
In addition to polyionic materials, a solution forming the tie
layer or part of it, can also contain additives. As used herein, an
additive can generally include any chemical or material. For
example, active agents, such as antimicrobials and/or
antibacterials can be added to a solution forming the tie layer,
particularly when used in biomedical applications. Some
antimicrobial polyionic materials include polyquaternary ammonium
compounds, such as those described in U.S. Pat. No. 3,931,319 to
Green et al. (e.g. POLYQUAD.RTM.).
Moreover, other examples of materials that can be added to a
solution forming the tie layer are polyionic materials useful for
ophthalmic lenses, such as materials having radiation absorbing
properties. Such materials can include, for example, visibility
tinting agents, iris color modifying dyes, and ultraviolet (UV)
light tinting dyes.
Still another example of a material that can be added to a solution
forming the tie layer is a polyionic material that inhibits or
induces cell growth. Cell growth inhibitors can be useful in
devices that are exposed to human tissue for an extended time with
an ultimate intention to remove (e.g. catheters or Intra Ocular
Lenses (IOL's), where cell overgrowth is undesirable), while cell
growth-inducing polyionic materials can be useful in permanent
implant devices (e.g. artificial cornea).
When additives are applied to a solution forming the tie layer,
such additives, preferably, have a charge. By having a positive or
negative charge, the additive can be substituted for one of the
polyionic materials in solution at the same molar ratio. For
example, polyquaternary ammonium compounds typically have a
positive charge. As such, these compounds can be substituted into a
solution of the present invention for the polycationic component
such that the additive is applied to a substrate material in a
manner similar to how a polycationic would be applied.
It should be understood, however, that non-charged additives can
also be applied to a substrate material of the present invention.
For example, in one embodiment, a polycationic layer can first
applied onto a substrate material. Thereafter, a non-charges
additive can be applied and immediately entrapped by a polyanionic
material applied thereon. In this embodiment, the polyanionic
material can sufficiently entrap the non-charged additive between
two or more layers of polyionic material. After such entrapment,
the substrate material can then be coated with other layers of
polyionic materials in accordance with the present invention.
As discussed above, a solution forming the tie layer can generally
be formed from polyionic materials and various other chemicals. In
one embodiment, a solution forming the tie layer is a single
component system that contains either a cationic or an anionic
material that is employed in successive applications. In another
embodiment, a solution forming the tie layer can be a
single-application, bicomponent solution that contains at least one
polycationic and one polyanionic material. In other embodiments,
the solution forming the tie layer can contain more than two
components of polyionic materials, such as 3, 4, 5, or more
components.
Regardless of the number of polyionic components present within a
single-application, in a bicomponent solution forming the tie
layer, it is typically desired that one of the polyionic components
of the solution be present in a greater amount than another
component such that a non-stoichometric solution can be formed. For
example, when a polyanionic/polycationic bicomponent solution is
formed, either one of the components can be present in an amount
greater than the other component. By forming a solution from
polyionic materials in such a manner, a substrate material can be
suitably coated with the tie layer solution in a single dip.
To control the amount of each polyionic component within a
single-application, bicomponent solution forming the tie layer, the
"molar charge ratio" can be varied. As used therein, "molar charge
ratio" is defined as the ratio of charged molecules in solution on
a molar basis. For example, a 10:1 molar charge ratio can be
defined as 10 molecules of a polyanion to 1 molecule of a
polycation, or 10 molecules of a polycation to 1 molecule of a
polyanion. The molar charge ratio can be determined as defined
above for any number of components within a solution, as long as at
least one polycation and one polyanion are included therein.
As the molar charge ratio is substantially increased, the structure
of the tie layer on a particular substrate can become more "open".
In some instances, such an opening of the tie layer structure can
result in the requirement of more dipping steps to achieve the
desired tie layer structure of the substrate material. In this
regard, a solution forming the tie layer typically has a "molar
charge ratio" of about 3:1 to about 100:1. In one embodiment, the
solution forming the tie layer has a molar charge ratio of about
5:1 (polyanion:polycation). In another embodiment, the solution
forming the tie layer has a molar charge ratio of about 1:5
(polyanion:polycation). In still another embodiment, a 3:1 or 1:3
molar charge ratio may be utilized.
In a certain embodiment, the solution forming the tie layer has a
molar charge ratio of about 10:1 (polyanion:polycation). By
employing a solution forming the tie layer having a predominant
amount of polyanionic material, a substrate material can be coated
in a manner such that the outer layer is a polyanionic material.
Substrates having an outer polyanionic material are typically more
acidic. It is believed that in some applications, an acidic outer
layer can provide a more hydrophilic substrate and allow better
wetting, thus allowing hydrophilic coating agents to approach the
substrate more intimately. This allows the process to proceed more
rapidly. However, it should be understood that an outer layer of
polycationic material may also be desirable. In contrast to a
polyanionic outer tie layer, a polycationic outer tie layer can be
achieved by providing a tie layer solution that contains a
predominant amount of polycationic material.
In accordance with the present invention, a solution forming the
tie layer, whether a single component solution for sequential
dipping or a multi-component for single dipping, the pH level is
typically maintained such that the solution remains stable. When
the pH of the solutions forming the tie layer is improperly varied,
a salt can sometimes form trough back-titration. Such precipitation
can often have an adverse affect on the ability of the tie layer
solution to coat the substrate layer as desired. As such, depending
on the particular solution used, the pH of the solution is normally
maintained at a value within about .+-.0.5 of the appropriate pH
range from the solution. In certain embodiments, the pH of the
solution forming the tie layer is maintained at a pH of .+-.0.1 of
the appropriate pH range for the solution. By maintaining the pH of
the solution within a specified range of the appropriate pH for the
solution, precipitation can be substantially inhibited.
The appropriate pH range for a solution forming the tie layer can
vary depending on the particular polyionic materials chosen. Any
suitable method known in the art can be utilized to determine the
appropriate pH range for a given solution. One such method is
described in "Controlling Bilayer Composition and Surface
Wettability of Sequentially Adsorbed Multilayers of Weak
Polyelectrolytes" by Dongsik Yoo, Seimel S. Shiratori, and Michael
R. Rubner, which is published in MACROMOLECULES.RTM. Volume 31,
number 13, pages 4309-4318 (1989). For example, in a particular
embodiment for multi-component solutions forming the tie layer, a
10:1 (polyanion:polycation) ratio of polyacrylic acid and
poly(allylamine hydrochloride) is utilized. For this particular
bicomponent solution forming the tie layer, the appropriate pH
range was determined to be about 2.5.
The formation and the application of layers forming the tie layer
onto the substrate surface may be accomplished according to various
processes. For example, the substrate material may be immersed in a
solution containing both an anionic polymer(s) and a cationic
polymer(s), or one or more layers each of the anionic polymer(s)
and cationic polymer(s) are successively deposited on the substrate
material surface, for example by dipping, spraying, printing,
spreading, pouring, rolling, spin coating or vacuum vapour
deposition, spraying or particularly dipping being preferred.
Following the deposition of one ionic polymer the bulk material may
be rinsed or dried before the deposition of the next ionic polymer
having opposite charges.
One particular dip method involves the steps of (i) applying a
layer of a first ionic polymer, for example of a cationic or an
anionic polymer to the bulk substrate material by immersing the
bulk material in a solution of the first ionic polymer; (ii)
optionally, rinsing the bulk material by immersing it in a rinsing
solution; (iii) optionally, drying said bulk material; and (iv)
applying a layer of a second ionic polymer having charges opposite
of the charges of the first ionic polymer, for example an anionic
or a cationic polymer, to the bulk material by immersing the bulk
material in a solution of the second ionic polymer.
A further dip method involves immersing the bulk material in a
multi-component solution comprising both the anionic and cationic
polymer.
Whether a single component solution for sequential dipping or a
multi-component for single dipping of the present invention, the
dip solutions of the present invention generally comprise the
respective polymer diluted in one or more different solvents.
Suitable solvents are, for example, water or an aqueous solution
comprising a water-miscible organic solvent, for example a C.sub.1
-C.sub.4 -alkanol such as methanol or ethanol; the preferred
solvent is pure water. The aqueous solutions of the cationic or
anionic polymer advantageously each have a slight acidic pH value,
for example a pH from about 2 to about 5 and preferably from about
2.5 to about 4.5. The concentrations of the dip solutions may vary
within wide limits depending, for example, on the particular ionic
polymer involved or the desired thickness. However, it may
generally be preferred to formulate relatively dilute solutions of
the ionic polymers. A particular anionic or cationic polymer
concentration is from about 0.0001 to about 0.25 weight percent,
from about 0.0005 to about 0.15 weight percent, from about 0.001 to
about 0.25 weight percent, from about 0.005 to about 0.01 weight
percent, from about 0.01 to about 0.05 weight percent and, in
particular, from 0.001 to 0.1 percent by weight, relative to the
total weight of the solution.
A suitable rinsing solution may be an aqueous solution. The aqueous
solution may have a pH of about 2 to about 7, from about 2 to about
5, or from about 2.5 to about 4.5.
Partial drying or removal of excess rinsing solution from the
surface between solution applications may be accomplished by a
number of means known in the art. While the bulk material may be
partially dried by merely allowing the coated material to remain in
an air atmosphere for a certain period of time, the drying time may
be accelerated by application of a mild stream of air to the
surface. The flow rate may be adjusted as a function of strength of
the material being dried and the mechanical fixturing of the
material.
The thickness of the tie layer may be adjusted during the formation
process by addition of one or more salts, such as sodium chloride
to the ionic polymer solution. A particular salt concentration that
may be employed is about 0.1 to about 2.0 weight percent. As the
salt concentration is increased, the polyionic material takes on a
more globular conformation. However, if the concentration is raised
to high, the polyionic material will not deposit well, if at all,
on the substrate surface.
The polymeric tie layer formation process may be repeated a
plurality of times, for example from 1 to about 50 times, from 1 to
about 24 times, from 1 to about 14 times, or only one time.
The immersion time for each of the coating and optional rinsing
steps may vary depending on a number of factors. In general, a
rinsing time of from about 30 seconds to about 30 minutes, from
about 1 to about 20 minutes, from about 1 to about 6 minutes may be
employed. The immersion in the polymer solutions may take place at
various temperatures, such as at room temperature or at a lower
temperature.
Instead of coating the substrate material by means of a dip
technique, the substrate may be coated using spray coating
techniques. The above given conditions and features concerning
solvents, concentrations, presence of salts, pH, temperature,
number and sequence of coating steps, and rinsing or drying steps
apply accordingly. Spray coating technique in this context
comprises any known process in the art including, for example,
conventional techniques of applying a fluid, or techniques using
ultrasonic energy, or electrostatic spray coating techniques. In
addition, a mixture of dip and spray techniques may also be
employed.
In this regard, an embodiment of the single-application,
bicomponent solution forming the tie layer can be prepared as
follows. However, it should be understood that the following
description is for exemplary purposes only and that a tie layer
solution of the present invention can be prepared by other suitable
methods.
A bicomponent solution forming the tie layer can be prepared by
first dissolving a single component polyanionic material in water
or other solvent at a designated concentration. For example, in one
embodiment, a solution of polyacrylic acid (PAA) having a molecular
weight of about 90,000 is prepared by dissolving a suitable amount
of the material in water to form a 0.001 M PAA solution. Once
dissolved, the pH of the polyanionic solution can be properly
adjusted by adding a basic or acidic material. In the embodiment
above, for example, a suitable amount of 1N hydrochloric acid (HCl)
can be added to adjust the pH to 2.5.
After preparing the polyanionic solution, the polycationic solution
can be similarly formed. For example, in one embodiment,
poly(allylamine hydrochloride) (PAH) having a molecular weight of
about 50,000 to about 65,000 can be dissolved in water to form a
0.001M solution. Thereafter, the pH can be similarly adjusted to
2.5 by adding a suitable amount of hydrochloric acid.
The above solutions can then be mixed to form a single-dip solution
for forming the tie layer of the present invention. In one
embodiment, for example, the solutions can be mixed slowly to
obtain the solution forming the tie layer. The amount of each
solution applied if the mix depends on the molar charge ratio
desired. For example, if a 10:1 (polyanion:polycation) solution is
desired, 1 part (by volume) of the PAH solution can be mixed into
10 parts of the PAA solution. After mixing, the solution can also
be filtered if desired.
Once the solution forming the tie layer is formed in accordance
with the present invention, it can then be applied to a substrate
material by any of the methods described above.
In some embodiments of the present invention, the particular
substrate material utilized can also be "pre-conditioned" or
"oriented" before being dipped into solution forming the tie layer.
Although not required, preconditioning the substrate material in
accordance with the present invention can enhance the growth of
polyionic layers in the "single dip" type process. In particular,
pre-conditioning a substrate material typically involves increasing
the roughness of the substrate surface.
In this regard, the roughness of the substrate surface can be
altered in a variety of ways. Generally, an "underlayer" or "primer
layer" of tie layer solution can be initially applied to the
substrate material to accomplish the desired surface alteration.
For example, in one embodiment, one or more standard layer-by-layer
dip coatings can be employed as an underlayer for the ultimate dip
coating of the present invention. The "underlayer" can be applied
by any method known in the art, such as by spray coating, dipping,
etc. In some embodiments, the underlayer can be made from a
polyionic material, such as poly(ethyleneimine). After applying
this primer coating or underlayer, in one embodiment, the substrate
can then be dipped into the ultimate coating solution. For
instance, in one embodiment, the ultimate coating solution can
contain poly(allylamine hydrochloride) and polyacrylic acid. In
still another embodiment, the solution forming the tie layer can
contain poly(allylamine hydrochloride) and sodium poly(styrene
sulfonate).
Moreover, in another embodiment, the substrate material can be
allowed to swell in a solvent solution containing a solvent and at
least one polyionic component. In general, any solvent that can
allow the components within the solution to remain stable in water
is suitable for use in the present invention. Examples of suitable
alcohols can include, but are not limited to, isopropyl alcohol,
hexanol, ethanol, etc. In certain embodiments, the substrate
material is first allowed to swell in an alcohol solution
containing about 20% isopropyl alcohol and about 80% water. In some
embodiments, the alcohol solution used to swell the substrate can
also be used as the solvent in the ultimate single-dip polyionic
tie layer solution.
After swelling, the substrate material can then be removed from the
solvent solution and allowed to "shrink". This "shrinking" step
causes the substrate material to entrap part or all of the initial
layer of the polycation or polyanion present within the solvent
solution. The swelling/entrapment process described in this
embodiment can enhance the ability of the solution forming the tie
layer to coat the substrate material.
However, it may often be desired to apply a tie layer having a
substantial thickness that cannot be sufficiently applied with a
single dip. For example, in one embodiment of the present
invention, a 500 angstrom tie layer (as measured by atomic force
microscopy ("AFM")) is applied to a substrate material in two
dipping steps. In particular, a 10:1. polyanion to polycation dip
is first applied to the substrate material. Thereafter, a 1:10
polyanion to polycation dip is employed as a second layer. In some
embodiments, more than two dips, such as 3 to 5 dips in
multi-component solutions of the present invention can be utilized.
For example, when coating a contact lens material according to the
present invention, three dips may be utilized.
The molecular weight of the anionic and cationic polymers used to
prepare the tie layers may vary within wide limits depending on the
desired characteristics such as adhesion on the bulk material,
coating thickness and the like. Generally, as the molecular weight
of the polyionic materials increases, the tie layer thickness
increases. However, if the increase in molecular weight is too
substantial, the difficulty in handling may also increase. In
general, a weight average molecular weight of from about 5,000 to
about 5,000,000, preferably from about 10,000 to 1,000,000, more
preferably from 15,000 to 500,000, even more preferably from 20,000
to 200,000 and in particular from 40,000 to 150,000, has proven as
valuable both for the anionic and cationic polymer(s) forming the
tie layer.
According to the above-mentioned methods, substrate materials are
obtained that comprise a tie layer of one or more polyelectrolytes
absorbed onto and/or heteropolarly bound on the surface. Due to
this modification, the surface is provided with functional groups
such as, for example, carboxy, sulfone, sulfato, phosphono or
phosphate groups or primary, secondary or tertiary amine groups. It
is these functional groups that may be further reacted with various
agents to form the surface-modified substrates of the present
invention.
According to step (b) of this invention bifunctional compounds
comprising an ethylenically unsaturated double bond are covalently
bound to the tie layer.
Bifunctional compounds comprising a polymerizable carbon-carbon
double bond to be coupled with functional groups of the tie layer
are, for example, compounds of formula: ##STR3## wherein R.sub.1 is
hydrogen, C.sub.1 -C.sub.4 -alkyl or halogen; R.sub.2 is hydrogen,
unsubstituted or hydroxy-substituted C.sub.1 -C.sub.6 -alkyl or
phenyl; R.sub.3 and R.sub.3 ' are each an ethylenically unsaturated
radical having from 2 to 6 C-atoms, or R.sub.3 and R.sub.3 '
together form a bivalent radical --C(R.sub.4).dbd.C(R.sub.4 ')--
wherein R.sub.4 and R.sub.4 ' are each independently of the other
hydrogen, C.sub.1 -C.sub.4 -alkyl or halogen; and (Alk*) is C.sub.1
-C.sub.6 -alkylene, and (Alk**) is C.sub.2 -C.sub.12 -alkylene.
The following preferences apply to the variables contained in
formulae (2a)-(2e): R.sub.1 is preferably hydrogen or C.sub.1
-C.sub.4 -alkyl, in particular hydrogen or methyl. R.sub.2 is
preferably hydrogen or hydroxy-C.sub.1 -C.sub.4 -alkyl, in
particular hydrogen or .beta.-hydroxyethyl. R.sub.3 and R.sub.3 '
are preferably each vinyl or 1-methylvinyl, or R.sub.3 and R.sub.3
' together form a radical --C(R.sub.4).dbd.C(R.sub.4 ')--; wherein
R.sub.4 and R.sub.4 ' are each independently hydrogen or methyl.
(Alk*) is preferably methylene, ethylene or 1,1-dimethyl-methylene,
in particular a radical --CH.sub.2 -- or --C(CH.sub.3).sub.2 --.
(Alk**) is preferably C.sub.2 -C.sub.4 -alkylene and in particular
1,2-ethylene.
Preferred vinyl monomers having a reactive group are
2-isocyanatoethylmethacrylate (IEM),
5,5-dimethyl-2-vinyl-oxazolin-4-one, acrylic acid, methacrylic
acid, acrylic anhydride, maleic acid anhydride,
2-hydroxyethylacrylate (HEA), 2-hydroxyethylmethacrylate (HEMA),
glycidylacrylate or glycidylmethacrylate, particularly preferred is
2-isocyanatoethylmethacrylate (IEM).
The method of attaching a bifunctional compound of formula
(2a)-(2e) to the tie layer depends on the nature of the reactive
groups being present in compounds (2a)-(2e) and at the surface of
the tie layer.
In case that a compound of formula (2a) has to be coupled to a tie
layer containing amino or hydroxy groups, the reaction may be
carried out in an inert organic solvent such as acetonitrile, an
optionally halogenated hydrocarbon, for example petroleum ether,
methylcyclohexane, toluene, chloroform, methylene chloride and the
like, or an ether, for example diethyl ether, tetrahydrofurane,
dioxane, or a more polar solvent such as DMSO, DMA,
N-methylpyrrolidone or even a lower alcohol or water, at a
temperature of from 0 to 100.degree. C., preferably from 0 to
50.degree. C. and particularly preferably at room temperature,
optionally in the presence of a catalyst, for example a tertiary
amine such as triethylamine or tri-n-butylamine,
1,4-diazabicyclooctane, or a tin compound such as dibutyltin
dilaurate or tin dioctanoate. In addition, the reaction of the
isocyanato groups with amino groups may also be carried out in an
aqueous solution in the absence of a catalyst. It is advantageous
to carry out the above reactions under an inert atmosphere, for
example under a nitrogen or argon atmosphere.
In case that a compound of formula (2a) has to be coupled to the
surface of a tie layer containing amino groups, the reaction may be
carried out advantageously at room temperature or at elevated
temperature, for example at about 20 to 75.degree. C., in water, in
a suitable organic solvent or mixtures thereof, for example in an
aqueous medium or in an aprotic polar solvent such as DMF, DMSO,
dioxane, acetonitrile and the like.
In case that a compound of formula (2b) has to be coupled to the
surface of a bulk material or to a natural or synthetic polymer
containing hydroxy groups, aprotic polar solvents are
preferred.
In case that a carboxy compound of formula (2c) has to be coupled
to a tie layer containing amino or hydroxy groups, or a hydroxy
compound of formula (2c) with carboxy groups of the surface, the
reaction may be carried out under the conditions that are customary
for ester or amide formation. It is preferred to carry out the
esterification or amidation reaction in the presence of an
activating agent, for example N-ethyl-N'-(3-dimethyl
aminopropyl)-carbodiimide (EDC), N-hydroxy succinimide (NHS) or
N,N'-dicyclohexyl carbodiimide (DCC).
In case that a compound of formula (2d) has to be coupled to a tie
layer containing amino or hydroxy groups, the reaction may be
carried out as described in organic textbooks, for example in an
aprotic solvent, for example one of the above-mentioned aprotic
solvents, at a temperature from room temperature to about
100.degree. C.
In case that a compound of formula (2e) has to be coupled to a tie
layer containing amino or hydroxy groups, the reaction may be
carried out, for example, at room temperature or at elevated
temperature, for example at about 20 to 100.degree. C., in an
aprotic medium using a base catalyst, for example, Al(O--C.sub.1
-C.sub.6 -alkyl).sub.3 or Ti(O--C.sub.1 -C.sub.6 -alkyl).sub.4.
The coating obtainable by steps (a) and (b) constitutes a "primary
coating" to which a "secondary coating" is attached in step (c). In
step (c), a hydrophilic monomer or a mixture of hydrophilic
monomers is graft polymerized onto the ethylenically unsaturated
double bonds introduced in step (b).
In this invention, the expression "hydrophilic monomer" is
understood to mean a monomer that typically produces as homopolymer
a polymer that is water-soluble or capable of absorbing at least
10% by weight water.
The hydrophilic monomers may be applied to the material surface and
polymerized there according to various known processes. For
example, the modified bulk material is immersed in a solution of
the hydrophilic monomer(s), or a layer of the monomer(s) is first
of all deposited on the modified bulk material surface, for example
by dipping, spraying, spreading, knife coating, pouring, rolling,
spin coating or vacuum vapor deposition. Preferably, a solution of
the hydrophilic monomer(s) in a suitable solvent, e.g. water, or in
a mixture of polar solvents is used.
Suitable hydrophilic monomers include, without the following being
an exhaustive list, hydroxy-substituted C.sub.1 -C.sub.2
-alkylacrylates, acrylic acid, acrylamide, methacrylamide, N-mono
or N,N-di-C.sub.1 -C.sub.2 -alkylacrylamide and methacrylamide,
ethoxylated acrylates and methacrylates, hydroxy-substituted
C.sub.1 -C.sub.2 -alkyl vinyl ethers, sodium ethylenesulfonate,
sodium styrenesulfonate, 2-acrylamido-2-methylpropanesulfonic acid,
N-vinyl-pyrrole, N-vinylsuccinimide, five- to seven-membered
N-vinyl lactams, 2- or 4-vinylpyridine, amino- (the term "amino"
also including quaternary ammonium), mono-C.sub.1 -C.sub.2
-alkylamino- or di-C.sub.1 -C.sub.2 -alkylamino-C.sub.1 -C.sub.2
-alkyl acrylates and methacrylates, allyl alcohol and the like.
Preferred hydrophilic monomers are acrylamide, acrylic acid,
methacrylic acid, hydroxyethyl methacrylate, hydroxyethyl acrylate,
methacrylamide, N,N-dimethylacrylamide, allylalcohol,
N-vinylpyrrolidone and N,N-dimethylaminoethyl acrylate.
Suitable polymerization initiators are known to the skilled artisan
and comprise, for example, persulfates, peroxides, hydroperoxides,
azo-bis(alkyl- or cycloalkylnitriles), percarbonates or mixtures
thereof. The use of persulfates is preferred.
After the polymerization, any non-covalently bound components, e.g.
non-reacted monomer(s), can be removed, for example by treatment
with suitable solvents.
It is believed that the grafts of one or more monomers in step (c)
create a so-called brush structure comprising a plurality of
polymer chains, which are covalently bound to the tie layer.
An additional valuable embodiment of the present invention is
provided, if in step (c) a hydrophilic monomer comprising a
reactive group, optionally in admixture with a further monomer, is
used.
In this embodiment, after the polymerization step according to (c),
(i) the reactive groups of the polymer chains may be reacted with a
further compound of formula (2a)-(2e) comprising an ethylenically
unsaturated double bond, followed by the (ii) graft polymerization
of a hydrophilic monomer and optionally a co-monomer having a
crosslinkable group onto the ethylenically unsaturated double bond,
and (iii) in case crosslinkable groups being present in step (ii),
crosslinking of said groups is initiated.
Hydrophilic monomers to be used in step (ii) comprise the same as
used in step (c). Preferred monomers are acrylic acid and/or
acrylic amide.
Suitable monomers having a crosslinking group include, without the
following being an exhaustive list, difunctionalized active esters,
such as ethylene glycolbis[sulfosuccinimidyl-succinate] and
bis[sulfosuccinimidyl]suberate,
sulfosuccinimidyl[4-azidosalicylamido]-hexanoate, difunctional
isocyanates, diacrylates such as 1,4-butanedioldiacrylate or
.alpha.,.omega.-PEG-diacrylate and diepoxides such as
ethyleneglycoldiglycidylether.
Alternatively, the crosslinking reaction can be switched such that
the NCO, acrylate, epoxide, etc. functionality is on the grafted
polymer, hence the crosslinking would be mediated by difunctional
amines such as ethylenediamine and the like.
The grafting of the hydrophilic monomers on the polymer chains of
the brush structure covalently attached to the tie layer according
to step (c) yields a coating having for example a so-called bottle
brush-type structure (BBT) composed of tethered "hairy" chains.
Such BBT structures in one embodiment comprise a long hydrophilic
backbone which carries relatively densely packed comparatively
short hydrophilic side chains. Polymeric coatings of said BBT
structures to a certain extent mimic highly water-retaining
structures occurring in the human body, for example in cartilage or
mucosal tissue.
The biomedical devices, e.g. ophthalmic devices obtained according
to the invention have a variety of unexpected advantages over those
of the prior art which make those devices very suitable for
practical purposes, e.g. as contact lens for extended wear or
intraocular lens. For example, they do have a high surface
wettability, which can be demonstrated by their contact angles,
their water retention and their water-film break up time or tear
film break up time (TBUT).
The TBUT plays a particularly important role in the field of
ophthalmic devices such as contact lenses. Thus the facile movement
of an eyelid over a contact lens has proven important for the
comfort of the wearer; this sliding motion is facilitated by the
presence of a continuous layer of tear fluid on the contact lens, a
layer, which lubricates the tissue/lens interface. However,
clinical tests have shown that currently available contact lenses
partially dry out between blinks, thus increasing friction between
eyelid and the lens. The increased friction results in soreness of
the eyes and reduced movement of the contact lenses. Now it has
become feasible to considerably increase the TBUT of commercial
contact lenses such as, for example, Lotrafilcon A lenses, by
applying a surface coating according to the invention. On the base
curve of a contact lens, the pronounced lubricity of the coating
facilitates the on-eye lens movement, which is essential for
extended wear of contact lenses. Moreover, the materials obtained
by the process of the invention provide additional effects being
essential for lenses for extended wear, such as an increased
thickness of the pre-lens tear film which contributes substantially
to low microbial adhesion and resistance to deposit formation. Due
to the extremely soft and lubricious character of the novel surface
coatings, biomedical articles such as in particular contact lenses
coated by the process of the invention show a superior wearing
comfort including improvements with respect to late day dryness and
long term (overnight) wear. The novel surface coatings moreover
interact in a reversible manner with ocular mucus, which
contributes to the improved wearing comfort.
EXAMPLES
In the examples, if not indicated otherwise, amounts are amounts by
weight, temperatures are given in degrees Celsius. Tear break-up
time values in general relate to the pre-lens tear film
non-invasive break-up time (PLTF-NIBUT) that is determined
following the procedure published by M. Guillon et al., Ophthal.
Physiol. Opt. 9, 355-359 (1989) or M. Guillon et al., Optometry and
Vision Science 74, 273-279 (1997). Average advancing and receding
water contact angles of coated and non-coated lenses are determined
with the dynamic Wilhelmy method using a Kruss K-12 instrument
(Kruss GmbH, Hamburg, Germany). Wetting force on the solid is
measured as the solid is immersed in or withdrawn from a liquid of
known surface tension. The molecular weight ("M.sub.w ") for the
polymers utilized is set forth as an approximation.
Example A
(Layer-by-layer Functionalization for Creating Thick PAAm
(Polyacrylamide) Tie Layers)
a) Iso-propanol-swollen Lotrafilcon A
(polysiloxane/perfluoroalkylpolyether copolymer) contact lenses
were dipped into a 0.13% PAA solution in water (MW of 90,000, pH of
2.5 by addition of HCl). The lenses were then thoroughly washed
with acetonitrile, treated with isocyanatoethyl methacrylate (IEM)
and then rinsed with water. The lenses were placed into a 5%
acrylamide solution (1 g acrylamide in 20 ml of water). Solution
and lenses were heated to 35.degree. C. and nitrogen was purged for
10 minutes. Sodium persulphate was added (40 mg per 20 milliliters
of solution). After 45 minutes, the lenses were washed in water
overnight and the coating was evaluated.
b) A branched version of the PAAm-coated lens was then made by
initially polymerizing with a 0.5% acrylic acid/4.5% acrylamide
solution. The lenses were then retreated with IEM and then
polymerized with acrylamide alone.
The resulting coated lenses were both highly lubricious and did not
take up Sudan black staining and did not attract dust. These
coatings proved to be abrasion resistant and, after finger rubbing
rewashing, appeared to be uniformly wettable and cleaning. After
autoclaving twice for 30 minutes each time, the lenses retained
their properties.
Example B
(Swell Dipped PAA/PAH) Activated Lenses)
Iso-propanol-swollen Lotrafilcon A
(polysiloxane/perfluoroalkylpolyether copolymer) contact lenses
were dipped into an aqueous bicomponent solution of PAA/PAH (0.07%
PAA with MW of 90,000 and 8.5 PPM of PAH having a MW of 50,000 to
65,000). The lenses were then water-rinsed and extracted with
acetonitrile. IEM (2 pipette drops per lens) was used to attach the
acrylate groups to the reactive polymeric layer. The lenses were
placed into an aqueous 5% acrylamide solution and polymerized as
described above in procedure b) of Example A.
A lubricious coating that was resistant to Sudan black staining was
produced. These characteristics did not change after two 30-minute
autoclaving cycles. These lenses withstood some finger rubbing
abrasion.
In addition, a branched version was made by co-polymerizing acrylic
acid with acrylamide (acrylic acid/acrylamide=1:9) and then washing
and extracting with acetonitrile followed by reattaching IEM to the
acrylic acid groups. After extraction of the lenses with water, a
second polymerization with acrylamide was performed, resulting in a
branched polyacrylamide structure.
Example C
(Swell Dipped PAA/PEI Activated Lenses)
Iso-propanol-swollen Lotrafilcon A
(polysiloxane/perfluoroalkylpolyether copolymer) contact lenses
were dipped into a 0.13% PAA solution (MW of 90,000, pH of 2.5
adjusted by HCl addition). After 5 minutes, the lenses were rinsed
with water and then dipped into a 0.044% PEI solution (MW of
70,000, pH of 3.5 adjusted by HCl addition). The lenses were washed
and extracted with acetonitrile, treated with isocyanatoethyl
methacrylate (IEM) and then extracted with water. The lenses were
placed into an aqueous 5% acrylamide solution and polymerized as
described above in procedure a) of Example A. Nitrogen purging was
performed and sodium persulphate was added at a rate of 40
milligrams per 20 milliliters of solution. The lenses were heated
at 35.degree. C. for 45 minutes. After this time, a viscous
solution had formed and the lenses were removed by washing in
excess water.
After overnight washing in water, the lenses were found to be
lubricious to the touch and resistant to Sudan black staining.
After autoclaving, the lenses continued to resist Sudan black
staining and remained lubricous.
* * * * *